Uphill running improves rat Achilles tendon tissue mechanical properties and alters gene expression without inducing pathological changes

Abstract

Little is known about the etiology of this disorder, and the development of a good animal model for overuse tendinopathy is essential for advancing insight into the disease mechanisms. Our aim was to test a previously proposed rat model for Achilles tendon overuse. Ten adult male Sprague-Dawley rats ran on a treadmill with 10°incline, 1 h/day, 5 days/wk (17-20 m/min) for 12 wk and were compared with 12 control rats. Histological, mechanical, and gene-expression changes were measured on the Achilles tendons after the intervention, and local tendon glucose-uptake was measured before and after the intervention with positron emission tomography. No differences were detected between runners and controls in tissue histology or in glucose uptake, indicating that tendon pathology was not induced. Greater tendon tissue modulus (P Ͻ 0.005) and failure stress/body weight (P Ͻ 0.02) in runners compared with controls further supported that tendons successfully adapted to uphill running. Several genes of interest were regulated after 12 wk of running. Expression of collagen III and insulin-like growth factor I was increased, while collagen I was unchanged, and decreases were seen in noncollagen matrix components (fibromodulin and biglycan), matrix degrading enzymes, transforming growth factor-␤1, and connective tissue growth factor. In conclusion, the tested model could not be validated as a model for Achilles tendinopathy, as the rats were able to adapt to 12 wk of uphill running without any signs of tendinopathy. Improved mechanical properties were observed, as well as changes in gene-expression that were distinctly different from what is seen in tendinopathy and in response to short-term tendon loading. loading; exercise; tendinopathy; collagen TENDONS TRANSMIT FORCE FROM muscle to bone during muscle contraction, and optimal, painless function of tendon tissue is essential in voluntary movement. Although tendons can withstand considerable force, repetitive movements can lead to overuse of tendon tissue, resulting in tendinopathy, which is characterized by pain during activity and significantly impaired performance (36). Tendinopathy is very common in relation to both sports and occupational loading (16,17,45), and, since treatment possibilities are still relatively poor, these conditions are often prolonged (36). Although the features of tendinopathy at the time point when symptoms occur are relatively well described, the etiology of overuse-related tendinopathy is still poorly understood. Thus we know that symptomatic human tendinopathy is characterized by histological changes, such as increased cell density, altered cell morphology, and disorganization of the collagen matrix (reviewed by Ref. 36). In addition, increased vascularization has been shown in tendinopathic tendon (8), and studies of gene expression commonly find higher levels of collagen I and III, proteoglycan, and matrix metalloproteinase (MMP)-2 mRNA, as well as decreased MMP-3 mRNA expression (3, 12-14, 26 -28). However, the events leading up to these chan...

Tendon development and musculoskeletal assembly: emerging roles for the extracellular matrix

“…These results point to a system by which the dynamics of fibril ultrastructure feedback on ECM production to modify tendon strength continuously. Tendon ECM and collagen fibrils are also continuously remodeled in response to mechanical forces, at least around the circumference of a tendon fascicle (Frolova et al, 2014;Heinemeier et al, 2012;Herchenhan et al, 2013;Kjaer, 2004;Pingel et al, 2014). TPCs in culture subjected to moderate mechanical forces show an increase in collagen fibril diameter, though diameter decreases with excessive mechanical force (De Almeida et al, 2010;Pingel et al, 2014).…”

The Achilles tendon: fundamental properties and mechanisms governing healing

“…However increasing the length of running episodes resulted in increased expression of both tendon, cartilage, and bone genes, indicating that excessive mechanical loading may cause metabolic changes and differentiation of TSCs into non-tenocyte lineages 20 . In a separate study, uphill running had a positive effects on tendon composition and mechanics, showing increased expression of collagen-3 and IGF-1, and decreased expression of fibromodulin, biglycan, degradative enzymes, TGF-β1, and CTGF 21 . Identifying changes in collagen synthesis in in vivo human studies has been more challenging.…”

“…el to explore how excessive loading may participate in Achilles tendinopathy has generated mixed histological results 21,73,[75][76][77] . These varied results 21,73,[75][76][77] suggest that the response of tendon to mechanical load is protocol dependent and that histological evidence alone is insufficient to fully characterize tendinopathy.…”

“…These varied results 21,73,[75][76][77] suggest that the response of tendon to mechanical load is protocol dependent and that histological evidence alone is insufficient to fully characterize tendinopathy. Determining the optimum loading conditions and the mechanisms by which this impacts tendon remodeling requires careful evaluation, with particular focus on load magnitude, frequency, and duration.…”

Achilles Tendon Injuries in Elite Athletes: Lessons in Pathophysiology from Their Equine Counterparts

“…Forced treadmill running has been used to try and generate tendon lesions in rodents that more accurately model the overuse situation occurring in the athlete. However, in addition to high individual variability in response, there has been significant variation between studies in terms of whether the AT is affected at all, adapts, or recovers with subsequent rest (it is uncertain whether the latter actually occurs in the case of spontaneous lesions) (Heinemeier et al 2012;Huang et al 2004;Jelinsky et al 2008). These variable results do not favor or justify the use of horses in similar studies.…”